Project Summary/Abstract Sickle cell disease (SCD) is caused by only a few mutations in the ?-hemoglobin gene (HBB). Individuals with the same mutation can have clinically quite different diseases, from mild with few clinical complications to severe complications such as stroke, leg ulceration, pulmonary hypertension, priapism, and acute chest syndrome. We propose to identify functional genetic variation that leads to the heterogeneity of SCD including ischemic stroke, hypertension, and elevated fetal hemoglobin in a cohort of 2,056 SCD patients from the REDS-III Brazilian SCD cohort. This deeply phenotyped cohort is undergoing whole genome sequencing (WGS) under the auspices of the NHLBI TOPMed program. The TOPMed program provides funding for WGS at the Baylor Genome Sequencing Center and genotype calling will be performed at Dr. Abecasis' lab at University of Michigan, but does not provide resources for analyses that combine WGS with clinical and end point data. The WGS data in this cohort provides a valuable opportunity to understand the genetics of the many comorbid conditions that bedevil SCD patients. This R21 is building on the work on the REDS-III study, which collected the Brazilian cohort between October 2013 and May 2015 to study aspects of transfusion such as determinants of response to transfusion, HIV infection, and alloimmunization. All the phenotypes to be studied here?ischemic stroke, blood pressure, and HbF levels?are secondary to the primary end points. We propose to study the genetics of ischemic stroke in HbSS/HbSB0 patients using whole genome, burden, pathway, and bioinformatics approaches with guidance from previous SCD stroke candidate gene and non- SCD genome-wide studies. We will further study the genetics of blood pressure and hypertension by focusing on all the known complex and Mendelian blood pressure loci (around 250). Finally, building on previous successful genome-wide studies of fetal hemoglobin levels, we will replicate reported findings and conduct genome-wide studies. The team pursuing this opportunity are all REDS-III investigators and pull together the WGS and bioinformatics expertise of Drs. Page (leader of the REDS-III bioinformatics and statistical genetics team), Sun, and Guo; and the disease and medical experience of Drs. Busch (transfusion medicine), Custer (U.S. PI of the Brazilian cohort; transfusion medicine), Shannon (SCD expert), Sabinio (Brazilian PI of the Brazilian co-cohort), and Rich (senior statistical geneticist) to understand and interpret these valuable resources data. They will also work with the TOPMed sickle cell phenotyping working group and other TOPMed investigators.